Association between clinically relevant toxicities of pazopanib and sunitinib and the use of weak CYP3A4 and P-gp inhibitors.

PURPOSE: Sunitinib and pazopanib, two tyrosine kinase inhibitors (TKI), may be targets of potential pharmacokinetic drug-drug interactions (P-PK-DDIs). While strong cytochrome P4503A (CYP3A4) inhibitors or inducers should cause a clinically relevant modification in plasma TKI concentrations, the effect of weak inhibitors is unknown. The objective of this study was to evaluate the association between weak P-PK-DDI and clinically relevant toxicity in real life. PATIENTS AND METHODS: This was a single-center retrospective study including patients treated with sunitinib or pazopanib for any malignancies, for whom a PK-DDI analysis was performed before starting TKI. The primary endpoint was the correlation between P-PK-DDIs and a dose decrease after 1 month of treatment. The secondary endpoint was the correlation between PK-DDIs and drug withdrawal due to toxicity. RESULTS: Seventy-six patients were assessed. A P-PK-DDI with weak CYP3A4 or P-gp inhibition was found in 14 patients. In patients with P-PK-DDI or without, the dose was reduced during the first month in 57.1% and 17.7% (p = 0.003) and the drug withdrawn in 42.8% and 11.3% (p = 0.011), respectively. In multivariate analysis, a significant correlation was found between P-PK-DDI (CYP3A4 and P-gp inhibitors) and dose reduction, and between drug withdrawal and PK-DDI (CYP3A4 inhibitors). CONCLUSION: P-PK-DDI was correlated with dose reduction and drug withdrawal due to toxicity. The causality of this relationship warrants to be assessed; therefore, therapeutic drug monitoring is necessary in patients treated with TKI.

Criticality at a Finite Strain Rate in Fluidized Soft Glassy Materials.

We study the emergence of critical dynamics in the steady shear rheology of fluidized soft glassy materials. Within a mesoscale elastoplastic model accounting for a shear band instability, we show how additional noise can induce a transition from a phase separated to homogeneous flow, accompanied by critical-like fluctuations of the macroscopic shear rate. Both macroscopic quantities and fluctuations exhibit power law behaviors in the vicinity of this transition, consistent with previous experimental findings on vibrated granular media. Altogether, our results suggest a generic scenario for the emergence of criticality when shear weakening mechanisms compete with a fluidizing noise.

Confinement-Induced Transition between Wavelike Collective Cell Migration Modes.

The structural and functional organization of biological tissues relies on the intricate interplay between chemical and mechanical signaling. Whereas the role of constant and transient mechanical perturbations is generally accepted, several studies recently highlighted the existence of long-range mechanical excitations (i.e., waves) at the supracellular level. Here, we confine epithelial cell monolayers to quasi-one-dimensional geometries, to force the establishment of tissue-level waves of well-defined wavelength and period. Numerical simulations based on a self-propelled Voronoi model reproduce the observed waves and exhibit a phase transition between a global and a multinodal wave, controlled by the confinement size. We confirm experimentally the existence of such a phase transition, and show that wavelength and period are independent of the confinement length. Together, these results demonstrate the intrinsic origin of tissue oscillations, which could provide cells with a mechanism to accurately measure distances at the supracellular level.

Opticin exerts its anti-angiogenic activity by regulating extracellular matrix adhesiveness.

Opticin is an extracellular matrix glycoprotein that we identified associated with the collagen network of the vitreous humor of the eye. Recently, we discovered that opticin possesses anti-angiogenic activity using a murine oxygen-induced retinopathy model: here, we investigate the underlying mechanism. Using an ex vivo chick chorioallantoic membrane assay, we show that opticin inhibits angiogenesis when stimulated by a range of growth factors. We show that it suppresses capillary morphogenesis, inhibits endothelial invasion, and promotes capillary network regression in three-dimensional matrices of collagen and Matrigel(TM). We then show that opticin binds to collagen and thereby competitively inhibits endothelial cell interactions with collagen via α(1)ß(1) and α(2)ß(1) integrins, thereby preventing the strong adhesion that is required for proangiogenic signaling via these integrins.

The vitreous glycoprotein opticin inhibits preretinal neovascularization.

PURPOSE: Opticin is an extracellular matrix glycoprotein that the authors discovered in the vitreous humor of the eye. It is synthesized by the nonpigmented ciliary epithelium and secreted into the vitreous cavity and, unusually for an extracellular matrix molecule, high-level synthesis is maintained into adult life. Here the authors investigated the hypothesis that opticin influences vascular development in the posterior segment of the eye and pathologic angiogenesis into the normally avascular, mature (secondary) vitreous. METHODS: Opticin was localized in murine eyes by immunohistochemistry. An opticin knockout mouse was established and vascular development was compared between knockout and wild-type mice. Wild-type and opticin null mice were compared in the oxygen-induced retinopathy model, a model of pathologic angiogenesis, and this model was also used to assess the effects of intravitreal injection of recombinant opticin into eyes of wild-type mice. RESULTS: Opticin colocalizes with the collagen type II-rich fibrillar network of the vitreous, the inner limiting lamina, the lens capsule, the trabecular meshwork, and the iris. Analyses of the hyaloid and retinal vasculature showed that opticin has no effect on hyaloid vascular regression or developmental retinal vascularization. However, using the oxygen-induced retinopathy model, the authors demonstrated that opticin knockout mice produce significantly more preretinal neovascularization than wild-type mice, and the intravitreal delivery of excess opticin inhibited the formation of neovessels in wild-type mice. CONCLUSIONS: A lack of opticin does not influence vascular development, but opticin is antiangiogenic and inhibits preretinal neovascularization.

Glycosidic enzymes enhance retinal transduction following intravitreal delivery of AAV2.

PURPOSE: To determine whether the co-injection of extracellular matrix degrading enzymes improves retinal transduction following intravitreal delivery of adeno-associated virus-2 (AAV2). METHODS: AAV2 containing cDNA encoding enhanced green fluorescent protein (GFP), under the control of a chicken ß-actin promoter, was delivered by intravitreal injection to adult mice in conjunction with enzymes including collagenase, hyaluronan lyase, heparinase III, or chondroitin ABC lyase. Two weeks later, retinal flatmounts were examined for GFP expression using confocal microscopy. RESULTS: Without the addition of enzymes, transduction was limited to occasional cells in the retinal ganglion cell layer. The addition of heparinase III or chondroitin ABC lyase greatly enhanced transduction of the retinal ganglion cell layer and increased the depth of transduction into the outer retina. Hyaluronan lyase had a limited effect and collagenase was ineffective. Electroretinograms survived with higher concentrations of heparinase III and chondroitin ABC lyase than were required for optimal retinal transduction. CONCLUSIONS: AAV2-mediated retinal transduction is improved by co-injection of heparinase III or chondroitin ABC lyase. Improved transduction efficiency may allow intravitreal injection to become the preferred route for delivering gene therapy to both the inner and outer retina.

Characterization of opticin and evidence of stable dimerization in solution.

Opticin is a class III member of the extracellular matrix small leucine-rich repeat protein (SLRP) family that was initially identified in the eye in association with the collagen fibrils of the vitreous humor. Recombinant and tissue-extracted forms of bovine opticin were subjected to biochemical and biophysical characterization. Following SDS-PAGE the predominant component produced by both forms was a broad band between 45-52 kDa. There was evidence for two-stage processing and, additionally, a proteolytic cleavage product of approximately 25 kDa. Deconvolution of circular dichroism spectra revealed beta-sheet (41%), beta-turn (21%), and alpha-helix (10%), and thermal denaturation experiments showed a transition with a midpoint of 47 degrees C. Weight-averaged molecular mass measurements using both light scattering and analytical ultracentrifugation demonstrated that opticin exists in solution as a stable dimer of approximately 90 kDa, which can be dissociated into a monomer by denaturation with 2.5 m guanidine hydrochloride or during SDS-polyacrylamide electrophoresis. Opticin remains a dimer after removal of the amino-terminal region by O-sialoglycoprotein endopeptidase digestion, suggesting that dimer formation is mediated by the leucine-rich repeats. Dimerization could have a number of functional consequences, including divalent ligand interactions.